Enhanced hippocampal long-term potentiation in rats after chronic exposure to homocysteine

Christie, Louisa A.; Riedel, Gernot; Algaidi, Sami A.; Whalley, Lawrence J.; Platt, Bettina

doi:10.1016/j.neulet.2004.09.072

Cited by 44 publications

(18 citation statements)

References 25 publications

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“…Animals were terminally anaesthetised with halothane, decapitated, brains removed, hippocampi dissected out and placed in ice-cold aCSF [68,69]. Hippocampal slices were prepared (*400 lm thick) using a McIlwain tissue chopper, and transferred to pre-warmed aCSF (37°C) where they remained for a minimum of 1 h before recording.…”

Section: Ex Vivo Slice Electrophysiologymentioning

confidence: 99%

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Polymeric alkylpyridinium salts permit intracellular delivery of human Tau in rat hippocampal neurons: requirement of Tau phosphorylation for functional deficits

Koss

Robinson

Mietelska‐Porowska

et al. 2015

Cell. Mol. Life Sci.

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Patients suffering from tauopathies including frontotemporal dementia (FTD) and Alzheimer's disease (AD) present with intra-neuronal aggregation of microtubule-associated protein Tau. During the disease process, Tau undergoes excessive phosphorylation, dissociates from microtubules and aggregates into insoluble neurofibrillary tangles (NFTs), accumulating in the soma. While many aspects of the disease pathology have been replicated in transgenic mouse models, a region-specific non-transgenic expression model is missing. Complementing existing models, we here report a novel region-specific approach to modelling Tau pathology. Local co-administration of the pore-former polymeric 1,3-alkylpyridinium salts (Poly-APS) extracted from marine sponges, and synthetic full-length 4R recombinant human Tau (hTau) was performed in vitro and in vivo. At low doses, Poly-APS was non-toxic and cultured cells exposed to Poly-APS (0.5 µg/ml) and hTau (1 µg/ml; ~22 µM) had normal input resistance, resting-state membrane potentials and Ca(2+) transients induced either by glutamate or KCl, as did cells exposed to a low concentration of the phosphatase inhibitor Okadaic acid (OA; 1 nM, 24 h). Combined hTau loading and phosphatase inhibition resulted in a collapse of the membrane potential, suppressed excitation and diminished glutamate and KCl-stimulated Ca(2+) transients. Stereotaxic infusions of Poly-APS (0.005 µg/ml) and hTau (1 µg/ml) bilaterally into the dorsal hippocampus at multiple sites resulted in hTau loading of neurons in rats. A separate cohort received an additional 7-day minipump infusion of OA (1.2 nM) intrahippocampally. When tested 2 weeks after surgery, rats treated with Poly-APS+hTau+OA presented with subtle learning deficits, but were also impaired in cognitive flexibility and recall. Hippocampal plasticity recorded from slices ex vivo was diminished in Poly-APS+hTau+OA subjects, but not in other treatment groups. Histological sections confirmed the intracellular accumulation of hTau in CA1 pyramidal cells and along their processes; phosphorylated Tau was present only within somata. This study demonstrates that cognitive, physiological and pathological symptoms reminiscent of tauopathies can be induced following non-mutant hTau delivery into CA1 in rats, but functional consequences hinge on increased Tau phosphorylation. Collectively, these data validate a novel model of locally infused recombinant hTau protein as an inducer of Tau pathology in the hippocampus of normal rats; future studies will provide insights into the pathological spread and maturation of Tau pathology.

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Section: Ex Vivo Slice Electrophysiologymentioning

confidence: 99%

“…Two responses recorded at 30-s intervals were averaged to provide a mean response per min and calculated relative to baseline (in percentage). The ex vivo recorded amplitude of the system-relevant output summed as population spike was used as a proxy for synaptic plasticity of hippocampal synapses [68][69][70].…”

Section: Ex Vivo Slice Electrophysiologymentioning

confidence: 99%

Polymeric alkylpyridinium salts permit intracellular delivery of human Tau in rat hippocampal neurons: requirement of Tau phosphorylation for functional deficits

Koss

Robinson

Mietelska‐Porowska

et al. 2015

Cell. Mol. Life Sci.

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“…Hcy also alters hippocampal plasticity and synaptic transmission resulting in learning and memory deficits [8,9]. Because elevated plasma Hcy levels known as hyperhomocysteinemia (HHcy) contribute to neurodegenerative diseases [10,11], homocysteine-decreasing therapies are potentially beneficial.…”

Section: Introductionmentioning

confidence: 99%

Betaine prevents homocysteine-induced memory impairment via matrix metalloproteinase-9 in the frontal cortex

Kunisawa

Nakashima

Nagao

et al. 2015

Behavioural Brain Research

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“…Also, Garcia, Haron, Pulman, Hua, and Freedman [32] have shown that higher levels of homocysteine are correlated with impaired performance in the Stroop test. Specifically, homocysteine was shown to be involved in episodic memory [3], [33], spatial learning [14], reversal learning [34], [35], and executive function [33]. On the other hand, studies have suggested homocysteine is perhaps not associated with other cognitive processes, including working memory and attention [33], although other studies reported that lowering homocysteine levels enhance working memory [36].…”

Section: Introductionmentioning

confidence: 99%

The Relationship between Associative Learning, Transfer Generalization, and Homocysteine Levels in Mild Cognitive Impairment

et al. 2012

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Previous studies have shown that high total homocysteine levels are associated with Alzheimer's disease (AD) and mild cognitive impairment (MCI). In this study, we test the relationship between cognitive function and total homocysteine levels in healthy subjects (Global Dementia Rating, CDR = 0) and individuals with MCI (CDR = 0.5). We have used a cognitive task that tests learning and generalization of rules, processes that have been previously shown to rely on the integrity of the striatal and hippocampal regions, respectively. We found that total homocysteine levels are higher in MCI individuals than in healthy controls. Unlike what we expected, we found no difference between MCI subjects and healthy controls in learning and generalization. We conducted further analysis after diving MCI subjects in two groups, depending on their Global Deterioration Scale (GDS) scores: individuals with very mild cognitive decline (vMCD, GDS = 2) and mild cognitive decline (MCD, GDS = 3). There was no difference among the two MCI and healthy control groups in learning performance. However, we found that individuals with MCD make more generalization errors than healthy controls and individuals with vMCD. We found no difference in the number of generalization errors between healthy controls and MCI individuals with vMCD. In addition, interestingly, we found that total homocysteine levels correlate positively with generalization errors, but not with learning errors. Our results are in agreement with prior results showing a link between hippocampal function, generalization performance, and total homocysteine levels. Importantly, our study is perhaps among the first to test the relationship between learning (and generalization) of rules and homocysteine levels in healthy controls and individuals with MCI.

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Enhanced hippocampal long-term potentiation in rats after chronic exposure to homocysteine

Cited by 44 publications

References 25 publications

Polymeric alkylpyridinium salts permit intracellular delivery of human Tau in rat hippocampal neurons: requirement of Tau phosphorylation for functional deficits

Polymeric alkylpyridinium salts permit intracellular delivery of human Tau in rat hippocampal neurons: requirement of Tau phosphorylation for functional deficits

Betaine prevents homocysteine-induced memory impairment via matrix metalloproteinase-9 in the frontal cortex

The Relationship between Associative Learning, Transfer Generalization, and Homocysteine Levels in Mild Cognitive Impairment

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